P-glypoprotein Inhibition Effect on the Pharmacokinetics of Two Tacrolimus Formulations: Prolonged and Extended-release

Summary

Tacrolimus is a drug administered orally available with different formulations: immediate release (Prograf®), prolonged-release (Advagraf®) and an extended-release one named LCP-Tacro (Envarsus®), formulated using the Melt-Dose process.

Tacrolimus is a lipophilic macrolide drug able to passive transmembrane diffusion. Its bioavailability displays a large interindividual variability, from 9 to 43%. Indeed, tacrolimus is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). P-gp is an efflux protein mainly located at the apex of the epithelia of the intestine, lymphocyte, kidney and blood-brain barrier. P-gp therefore limits the intestinal resorption of tacrolimus and also its diffusion into its target compartment (i.e the lymphocyte. The expression of this protein is different throughout the digestive tract with maximum expression at the ileal level. CYP3A4 is a coenzyme that is responsible of more than 90% of the metabolism of tacrolimus, at the digestive and hepatic level. Both P-gp and CYP3A4 play a role in tacrolimus absorption/diffusion process.

A new formulation of tacrolimus, LCP-Tacro, (Envarsus®) was approved in 2014. Its efficacy was compared to Prograf® in two phase III de novo or switch Prograf® trials in kidney transplantation.

With tacrolimus, there is a strong inter-individual pharmacokinetic variability which, to date, has not been fully characterized. Variations in bioavailability may partly explain this high variability. The different formulations are resorbed at distinct gastrointestinal sites which could explain different absorptions between Prograf/Advagraf and LCP-Tacro forms.

These findings raise the question of the role of P-gp in explaining the difference in bioavailability between formulations. The use of a P-gp inhibitor could therefore have a different impact on exposure to different galenic formulations.

Verapamil is an inhibitor of P-gp and CYP 3A4, which is frequently prescribed and recommended by FDA for drug-drug interaction studies aiming at evaluating P-gp substrates, used in healthy volunteers at dosages up to 240 mg/D13-14. Otherwise, verapamil-tacrolimus interaction has been characterized in vitro.

It has also been shown that inhibitory effect of verapamil at a single dose of 120 mg administered one hour prior to the administration of a P-gp substrate exhibited an optimum power of inhibition.

The safety of Advagraf® and Envarsus® administrations have already been subjected to several phase I trials in healthy volunteers reinforcing the knowledge of their safety profile.

The aim of the study is to compare the interaction profile of Advagraf® and Envarsus® when co-administered with verapamil in healthy subjects and to provide guidelines on tacrolimus dosage adjustment in such cases.

Conditions

• Pharmacokinetics

Interventions

DRUG

Treatment A

Administration of a 3 mg dose of prolonged-release tacrolimus (Advagraf®)

DRUG

Treatment B

Administration of a 2 mg dose of LCP-tacro (Envarsus®)

DRUG

Treament C

Administration of a single 120 mg dose of immediate-release verapamil (Isoptine®) and a 3 mg dose of prolonged-release tacrolimus (Advagraf®)

DRUG

Treatment D

Administration of a single 120 mg dose of immediate release verapamil (Isoptine®) and a 2 mg dose of LCP-tacro (Envarsus®)

BIOLOGICAL

Pharmacocinetik

Nine sampling points of 7 ml each will be taken on the first day at the CIC UIC and the last sampling point will be carried out at 24 hours from the administration the following morning.

GENETIC

Genetic

A genetic analysis to determine your characteristics for enzymes in your metabolism as well as transport proteins will be carried out. An additional 7 ml blood tube will be drawn for this purpose during the first period.

OTHER

Selection visit:

During this visit, it will be asked to sign the following consent and it will be carried out: * a clinical examination (questioning and physical examination with measurement of height and weight); * a blood test (18 mL); * a blood pregnancy test if you are a woman; * a cardiac assessment (electrocardiogram). These results should be normal.

Sponsors & Collaborators

• Rennes University Hospital

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

OTHER

Masking

SINGLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2022-02-15

Primary Completion

2023-05-16

Completion

2023-05-16

Countries

• France

Study Locations